Sepsis syndrome results from an exaggerated cascade of inflammation initiated by complex interactions between an infectious organism and host immune, inflammatory, and coagulation responses (Hotchkiss and Karl (2003) N Engl J Med 348:138). Inflammatory agonists elevated during sepsis, including TNF-α and thrombin, increase permeability in endothelial monolayers. Increased systemic vascular permeability leads to redistribution of fluid and solutes to extravascular compartments, resulting in hypovolemia, hemoconcentration, and hemostasis.
Over 650,000 cases of sepsis are diagnosed a year with 20 to 50 percent mortality, making sepsis the most common cause of death among hospitalized patients in non-coronary intensive care units. Though it is generally accepted that host response (involving multiple cell types, inflammatory mediators, and coagulation factors) determines sepsis-associated mortality, clinical trials have largely failed to identify effective therapeutic targets. Molecular mechanisms underlying the development and maintenance of sepsis remain poorly understood and effective pharmacologic targets for these severe disease syndromes have not been identified.
As indicated above, sepsis is characterized by increased vascular permeability in response to an exaggerated inflammatory cascade. Solutes pass through an endothelial barrier via paracellular pathways or through receptor-mediated transcytosis (Michel (1992) Am Rev Respir Dis 146:S32; Renkin (1985) J Appl Physiol 58:315). Current general consensus is that paracellular pathways are primarily responsible for the increased vascular permeability seen in acute inflammatory disease states (Groeneveld (2002) Vascul Pharmacol 39:247; Bernard et al. (1994) Am J Respir Crit. Care Med 149:818). One frequently cited model suggests that paracellular gaps form due to imbalanced competition between cytoskeletal, adhesive cell-cell, and cell-matrix forces. In this model, cytoskeletal filamentous (F)-actin polymerizes into morphologically distinct stress fibers which transmit actomyosin-generated tension between cell junctions and focal adhesions. Focal adhesions (FA) are large macromolecular assemblies that link the actin cytoskeleton to the extracellular matrix (ECM) and localize signaling proteins to sites of integrin binding and clustering.
The present disclosure reveals integrins αvβ5 and αvβ3 as important regulators of endothelial barrier function in response to inflammatory agonists. Surprisingly, these closely related integrins support opposing cellular mechanisms that lead to differential organization of permeability-inducing (αvβ5 and actin stress fibers) and barrier-enhancing (αvβ3 and cortical actin) cytoskeletal structures. We report here the unexpectedly distinct roles of integrins αvβ5 and Δvβ3 in the regulation of vascular permeability in sepsis.